Imtiyaz Hongxia Z, Rosenberg Stephen, Zhang Yuhang, Rahman Ziaur S M, Hou Ying-Ju, Manser Tim, Zhang Jianke
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
J Immunol. 2006 Jun 1;176(11):6852-61. doi: 10.4049/jimmunol.176.11.6852.
The Fas-associated death domain protein (FADD)/Mort1 is a signaling adaptor protein which mediates the activation of caspase 8 during death receptor-induced apoptosis. Disruption of FADD in germ cells results in death receptor-independent embryonic lethality in mice. Previous studies indicated that in addition to its function in apoptosis, FADD is also required in peripheral T cell homeostasis and TCR-induced proliferative responses. In this report, we generated B cell-specific FADD-deficient mice and showed that deletion of FADD at the pro-B cell stage had minor effects on B cell development in the bone marrow, and resulted in increased splenic and lymph node B cell numbers and decreased peritoneal B1 cell numbers. As in T cells, a FADD deficiency inhibited Fas-induced apoptosis in B cells. However, B cell-proliferative responses induced by stimulation of the BCR and CD40 using anti-IgM or anti-CD40 Abs were unaffected by the absence of FADD. Further analyses revealed that FADD-deficient B cells were defective in proliferative responses induced by treatments with dsRNA and LPS which stimulate TLR3 and TLR4, respectively. Therefore, in addition to its apoptotic function, FADD also plays a role in TLR3- and TLR4-induced proliferative responses in B cells.
Fas相关死亡结构域蛋白（FADD）/Mort1是一种信号衔接蛋白，在死亡受体诱导的细胞凋亡过程中介导半胱天冬酶8的激活。生殖细胞中FADD的破坏会导致小鼠出现与死亡受体无关的胚胎致死性。先前的研究表明，FADD除了在细胞凋亡中发挥作用外，在外周T细胞稳态和TCR诱导的增殖反应中也是必需的。在本报告中，我们构建了B细胞特异性FADD缺陷小鼠，并表明在前B细胞阶段缺失FADD对骨髓中的B细胞发育影响较小，导致脾脏和淋巴结B细胞数量增加，腹膜B1细胞数量减少。与T细胞一样，FADD缺陷会抑制B细胞中Fas诱导的细胞凋亡。然而，使用抗IgM或抗CD40抗体刺激BCR和CD40所诱导的B细胞增殖反应不受FADD缺失的影响。进一步分析表明，FADD缺陷的B细胞在分别刺激TLR3和TLR4的双链RNA和LPS处理诱导的增殖反应中存在缺陷。因此，除了其凋亡功能外，FADD在B细胞中TLR3和TLR4诱导的增殖反应中也发挥作用。
